Monobody Therapy for Gynecologic Cancers Endometrial cancer is the most common gynecologic cancer in the western world. Systemic treatments for advanced disease have traditionally included hormonal therapy and chemotherapy. Responses to treatment are short-lived, and advanced-stage disease remains incurable. Ovarian cancer is the eighth most common cancer and causes more deaths than any other gynecologic cancer. Increasing evidence implicates prolactin (PRL) as a key factor in endometrial and ovarian cancer. Elevated levels of circulating PRL in gynecologic cancer suggest a role for PR L in endometrial and ovarian carcinogenesis. Recent studies have found significantly elevated expression of PRL in women with a strong family history of ovarian cancer. In addition, PRL receptor (PRLR) expression is upregulated in endometrial tumors, as well as in premalignant endometrial hyperplasia. Recent histochemical data found PRLR expression in >80% of ovarian tumors, but in none of the normal ovarian tissues tested. Increased expression of both PRLR and PRL mRNA in endometrial tumors indicates the importance of autocrineiparacrine signaling by extra pituitary PRL in tumor tissues. PRL induces proliferation in ovarian and endometrial cancer cell lines, and promotes malignant transformation of normal ovarian epithelial cells through activation of Ras. PRL-transformed cells acquire the ability to grow in soft agar and to form tumors in a SCID mouse model. These data validate PRL as a therapeutic target in endometrial and ovarian cancer. The overall goal of this project is to develop and characterize a human anti-PRLR monobody as an innovative treatment for gynecologic cancer. An anti-PRLR monobody will be a best-inclass inhibitor of PRLR signaling because unlike conventional antibodies or ligand-based biomolecules it is incapable of dimerizing PRLR thereby preventing adventitious initiation of signaling. In Phase I, we will identify a high-affinity anti-PRLR monobody from our phage display library. Clones will be rank-ordered by their affinity and specificity for PRLR. Finally, we will evaluate function in vitro andin a murine tumor model. Successful identification of a monobody with a nanomolar Kd, high specificity for PRLR, and ability to suppress tumor growth in vivo, will merit submission of a Phase II application. Phase II work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as animal studies to demonstrate efficacy, will be performed.